The purpose of the studies proposed is to examine the relationship between hepatic plasma membrane lipid composition and fluidity and insulin receptor development in fetuses obtained from an animal model of diabetic pregnancy. Insulin receptors are present in increased numbers on fetal tissues when compared to adults. Furthermore, in the presence of hyperinsulinemia, there is paradoxical up-regulation of fetal insulin receptors in diabetic pregnancy. This results in greatly increased insulin sensitivity which is manifested by rapid and sometimes fatal hypoglycemia following birth. Membrane fluidity has been shown to influence the behavior of insulin receptors in a variety of situations. Membrane fluidity is itself dependent upon lipid composition of the membrane; several factors including increased phospholipid/protein ratios, decreased lecithin/sphingomyelin ratio, and increased fatty acid unsaturation of membrane lipids result in increasing membrane fluidity. It has been shown that membrane lipid composition changes during fetal development, and preliminary data by this investigator suggests that membrane lipid composition is altered by fetal hyperinsulinemia. We will examine the changes in membrane fluidity by the technique of fluorescence polarization during normal and diabetic gestation. The effects of insulin on membrane fluidity will be examined directly as well as by assessing changes in membrane lipid composition of whole cells (thymocytes) following the addition of insulin. We propose that observation of increased insulin receptors in fetal tissues is due to increased rigidity of the membrane and that down-regulation of receptors in fetal tissues is limited by the physicial structure of the membrane. The results from these studies will provide greater understanding of the disturbances in fetal development which occur in diabetic pregnancies and may improve our current therapeutic approach to these problems.